DESCRIPTION: This is a revised application that will study hereditary nonpolyposis colorectal cancer (HNPCC). The majority of HNPCC is considered to be due to germline mutations and DNA mismatch repair (MMR) genes which include hMSH2, hMlH1, hPMS1, hPMS2, and GTBP. The author, as well as other investigators, have noticed that HNPCC is inherited in an autosomal dominant fashion and accounts for 5-10% of all cases of colorectal carcinoma. Mutation in MMR leads to deficient DNA mismatch repair, which subsequently leads to the accumulation of mutations that are detected by defects in tandem repeats of DNA. Replication errors (RERs) appear in microsatellite repeat fragments. The applicant proposes studies to test the hypothesis that significant variation among and within HNPCC families leads to the differences in age and spectrum of tumors observed in HNPCC. She has assembled a number of investigators and families and will approach this problem through four specific aims. The first is to test for associations between specific mutations in MMR genes and variations of the tumor spectrum and age-associated risk for cancer. The second specific aim is to determine whether mutations or base changes in MMR genes cause HNPCC with its associated carcinomas in families that do not meet the rigid Amsterdam criteria. The third specific aim is to determine whether polymorphisms in genes that are associated with increased risk of sporadic colorectal carcinomas in glutathione S-transferase M1 (GSTM1) or N-acetyltransferase 2 (NAT2) affect risk for cancer in MMR carriers. The fourth specific aim is to identify families that meet the Amsterdam criteria but are RER-.